The objective of this project is a biochemical and molecular analysis of hormonal regulation of tPA and its major physiological inhibitor, PAI-1, in rat hepatoma cells and hepatocytes in tissue culture. The first and major aim is an analysis of the molecular basis of posttranscriptional down- regulation of PAI-1 gene expression in HTC cells by cyclic nucleotides. The second aim is to examine mechanisms of transcriptional silencing important for the down-regulation of PAI-1 gene expression in HTC cells. The third aim will define the molecular basis for the synergistic induction of tPA gene transcription by glucocorticoids and cyclic nucleotides in HTC cells, and will also investigate the antagonistic actions of these hormones in primary cultures of normal rat hepatocytes.